The effect of chronic pyridostigmine administration on pyridostigmine‐
            <sup>14</sup>
            C metabolism in myasthenia gravis

Kornfeld, Peter; Wolf, Robert L.; Samuels, Arthur J.; Osserman, Kermit E.

doi:10.1212/wnl.21.5.550

Cited by 8 publications

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“…PB does not cross the blood-brain barrier presumably because it has a positive charge on th e pyridnyl nitrogen (Birtley et al, 1966). The major metabolic product of PB is 3-hydroxy-N-methylpyridium resulting from the carbamate hydrolysis that abolishes its cholinergic action (Kornfeld et al, 1970(Kornfeld et al, , 1971. The half-life valu e o f pyridostigmine administered iv in humans is 1-2 h (Eiermann et al, 1993).…”

mentioning

confidence: 99%

Neurotoxicity Resulting From Coexposure to Pyridostigmine Bromide, Deet, and Permethrin: Implications of Gulf War Chemical Exposures

Abou‐Donia¹

1996

Journal of Toxicology and Environmental Health

254

109

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Of the three-quarters of a million service personnel involved in the Persian Gulf War, approximately 30,000 have complained of neurological symptoms of unknown etiology. One contributing factor to the emergence of such symptoms may be the simultaneous exposure to multiple agents used to protect the health of service personnel, in particular, the anti-nerve agent pyridostigmine bromide (PB; 3-dimethylaminocarbonyloxy-N-methylpyridinium bromide), the insect repellent DEET (N,N-diethyl-m-toluamide), and the insecticide permethrin (3-(2,2-dichloro-ethenyl)-2,2-dimethylcyclopropanecarboxylic acid (3-phenoxyphenyl)methyl ester). This study investigated neurotoxicity produced in hens by individual or simultaneous exposure to these agents (5 d/wk for 2 months to 5 mg/kg/d PB in water, po; 500 mg/kg/d DEET, neat, sc; and 500 mg/kg/d permethrin in corn oil, sc). At these dosages, exposure to single compounds resulted in minimal toxicity. Combinations of two agents produced greater neurotoxicity than that caused by individual agents. Neurotoxicity was further enhanced following concurrent administration of all three agents. We hypothesize that competition for liver and plasma esterases by these compounds leads to their decreased breakdown and increased transport of the parent compound to nervous tissues. Thus, carbamylation of peripheral esterases by PB reduces the hydrolysis of DEET and permethrin and increases their availability to the nervous system. In effect, PB "pumps" more DEET and permethrin into the central nervous system. Consistent with this hypothesis, hens exposed to the combination of the three agents exhibited neuropathological lesions with several characteristics similar to those previously reported in studies of near-lethal doses of DEET and permethrin. If this hypothesis is correct, then blood and liver esterases play an important "buffering" role in protecting against neurotoxicity in the population at large. It also suggests that individuals with low plasma esterase activity may be predisposed to neurologic deficits produced by exposure to certain chemical mixtures.

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mentioning

confidence: 99%

Neurotoxicity Resulting From Coexposure to Pyridostigmine Bromide, Deet, and Permethrin: Implications of Gulf War Chemical Exposures

Abou‐Donia¹

1996

Journal of Toxicology and Environmental Health

254

109

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“…In a specially designed study to investigate such interactions, no differences in plasma concentrations of neostigmine and pyridostigmine were found, irrespective of whether the drugs were administered alone or simultaneously (Aquilonius et al 1983). Kornfeld et al (1971) found that long term treatment with pyridostigmine affected neither the plasma concentration-time curve of 14C-pyridostigmine nor the urinary pattern of excreted drug and metabolites.…”

Section: Other Cholinesterase Inhibitorsmentioning

confidence: 83%

“…Among these, paper chromatography (Nowell et al 1962b) and spectrophotometry (Coper et al 1974;Nowell et al 1962a) are not sufficiently sensitive for analysis in plasma after administration of therapeutic doses of the drugs. Radioisotopic studies (Kornfeld et al 1970(Kornfeld et al , 1971Somani et al 1972) have also been used, but suffer from low selectivity.…”

Section: Reversible Cholinesterase Inhibitorsmentioning

confidence: 99%

“…Kornfeld et al (1971) investigated the kinetics of radioactivity in the blood and urine following intravenous administration of 14C-pyridostigmine and suggested the occurrence of trapping mechanisms in a tissue compartment, but their results are open to other interpretations.…”

Section: Distributionmentioning

confidence: 99%

“…Other metabolites have also been detected in the plasma and urine and their tentative structures have demonstrated the formation of hydroxy, quinone and demethylated metabolites and their corresponding glucuronides (Kornfeld et al 1970;Somani et al 1972). After intravenous administration of 14C-pyridostigmine, approximately 90% of the radioactivity administered was recovered in the urine, although traces of 14C-pyridostigmine were detected in the plasma 6 to 8 hours after admin-241 istration (Kornfeld et al 1971). Somani et al (1972) found that during a 24-hour period after administration pyridostigmine was excreted in the urine as the unchanged drug and its main metabolite in a ratio of 4 : 1, in accordance with findings by Nowell et al (1962a).…”

Section: Neostigmine and Pyridostigminementioning

confidence: 99%

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Clinical Pharmacokinetics of Cholinesterase Inhibitors

Aquilonius

Hartvig

1986

Clinical Pharmacokinetics

101

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This review deals mainly with the pharmacokinetics of the reversible quaternary cholinesterase inhibitors neostigmine, pyridostigmine and edrophonium, which are mainly used to antagonise non-depolarising neuromuscular blockade in general anaesthesia and in the symptomatic treatment of myasthenia gravis. Only in the last few years, since the introduction of highly sensitive and selective analytical procedures based on gas and liquid chromatography, have proper pharmacokinetic studies of these drugs become possible. Rapid cooling and addition of internal standard to samples before freezing are important precautions in view of the poor stability of the cholinesterase inhibitors in plasma and blood. Plasma clearances of the reversible quaternary cholinesterase inhibitors are in the range 0.5 to 1.0 L/h/kg and their apparent volumes of distribution range from 0.5 to 1.7 L/kg. Accordingly, the drugs have short plasma elimination half-lives, in the order of 30 to 90 minutes. One to two hours after oral administration of 60 mg pyridostigmine, peak plasma concentrations of 40 to 60 micrograms/L are observed, whereas the plasma concentrations of neostigmine after a 30 mg oral dose are only 1 to 5 micrograms/L. The oral bioavailability of these hydrophilic ionised compounds is low: that of pyridostigmine is approximately 10% and the value for neostigmine is even lower. In spite of the short elimination half-life of pyridostigmine, intraindividual variations in plasma concentration during a dose interval are small in myasthenic patients receiving oral maintenance therapy, probably as a result of slow absorption from the gastrointestinal tract. Severely impaired renal function has been shown to prolong the elimination of neostigmine and pyridostigmine, while methylcellulose has been reported to inhibit the absorption of the latter drug completely. Other pharmacokinetic drug interactions suggested so far do not seem to be of clinical significance. Although a positive correlation has been demonstrated between the plasma concentrations of these drugs and their pharmacological effects as measured by a decrement in muscle response to repetitive nerve stimulation in a single muscle, this relationship is less clear when a global evaluation of muscular function in myasthenia gravis is used. Pharmacokinetic studies of the tertiary reversible cholinesterase inhibitor physostigmine, an important tool in experimental cholinergic neuropharmacology, are still in their initial stages. This drug too is characterised by a short plasma elimination half-life of 20 to 30 minutes.(ABSTRACT TRUNCATED AT 400 WORDS)

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Pharmacokinetics of ambenonium, a reversible cholinesterase inhibitor, in rats

Yamamoto

Kohda

Sawada

et al. 1991

Biopharm & Drug Disp

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The pharmacokinetics of ambenonium, a reversible cholinesterase inhibitor, in rats was investigated following intravenous administration of the drug. Mean residence time and steady state volume of distribution were 23-36 min and 0.20-0.311 kg-1, respectively, and were dose independent at the dose of 0.3-3 mumole kg-1. Total body clearance of 8.2 ml min-1 kg-1 over 0.3 mumole kg-1 was slightly increased to 11.3 ml min-1 kg-1 at 3 mumole kg-1. Renal clearance was also increased with the increase of the dose, while hepatobiliary clearance was substantially constant. Ambenonium was highly concentrated in the liver, kidney, spleen, and lung. About 30 per cent of the dose is concentrically stored in the liver at 6 h after administration, and had not disappeared after 24 h.

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The effect of chronic pyridostigmine administration on pyridostigmine‐ ¹⁴ C metabolism in myasthenia gravis

Cited by 8 publications

References 0 publications

Neurotoxicity Resulting From Coexposure to Pyridostigmine Bromide, Deet, and Permethrin: Implications of Gulf War Chemical Exposures

Neurotoxicity Resulting From Coexposure to Pyridostigmine Bromide, Deet, and Permethrin: Implications of Gulf War Chemical Exposures

Clinical Pharmacokinetics of Cholinesterase Inhibitors

Pharmacokinetics of ambenonium, a reversible cholinesterase inhibitor, in rats

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The effect of chronic pyridostigmine administration on pyridostigmine‐ 14 C metabolism in myasthenia gravis

Cited by 8 publications

References 0 publications

Neurotoxicity Resulting From Coexposure to Pyridostigmine Bromide, Deet, and Permethrin: Implications of Gulf War Chemical Exposures

Neurotoxicity Resulting From Coexposure to Pyridostigmine Bromide, Deet, and Permethrin: Implications of Gulf War Chemical Exposures

Clinical Pharmacokinetics of Cholinesterase Inhibitors

Pharmacokinetics of ambenonium, a reversible cholinesterase inhibitor, in rats

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The effect of chronic pyridostigmine administration on pyridostigmine‐ ¹⁴ C metabolism in myasthenia gravis